Molecular Genetics of Nail–Patella Syndrome

Abstract

Nail–patella Syndrome (NPS) is a pleiotropic disorder affecting development of the limbs, kidneys, eyes and central nervous system, which is the result of heterozygous, loss‐of‐function mutations in the transcription factor, LIM‐homeobox 1β (LMX1B). There is no correlation between the type or nature of individual mutations and the severity of the phenotype. The availability of animal models, together with analysis of gene expression patterns during development, has substantiated that the range of clinically relevant signs and symptoms is greater than appreciated previously. Evidence is building that attention deficit±hyperactivity disorder and depression may be constituent parts of the syndrome. The variation in the range and severity of symptoms, and the diverse range of affected tissues, make NPS an appropriate model in which to study the effects of gene interactions on the observed phenotype.

Key Concepts:

  • NPS is a pleiotropic, clinically variable autosomal dominant disorder.

  • LMX1B is a member of a gene family primarily involved in regulating neuronal patterning.

  • Loss of function mutations in LMX1B cause NPS but do not predict disease severity.

  • Analysis of Lmx1b expression has helped explain previously unknown neural aspects of NPS.

  • Physicians should be aware of the extra‐skeletal aspects of NPS and institute appropriate monitoring and treatment.

Keywords: nail–patella syndrome; LMX1B; mutations; pleiotropy; central nervous system

Figure 1.

The ‘classic tetrad’ of NPS. (a) Nail dysplasia: Left hand upper panels, right hand lower panels. Note that dysplasia is more severe on the thumb and becomes milder from thumb to fifth finger. Note also the absence of creases over the distal interphalangeal joints. (b) Knee dysplasia. A fixed dislocation of the patella is seen on the right knee, with patellar aplasia on the left. (c) Elbow dysplasia. Note pterygia of left elbow at full extension. Note also poor development of muscle in upper arms. (d) Pelvic X‐ray showing bilateral iliac horns (arrows).

Figure 2.

Missense mutations (• below the gene) are clustered within the LIM and homeodomains of LMX1B. They always change highly conserved residues. Nonsense (X), frameshift (Δ) and splice (□) mutations, which prevent synthesis of a full‐length protein, also tend to be grouped in these regions. It is not known why there are no NPS mutations downstream of the homeodomain.

Figure 3.

Expression of Lmx1b during mouse development as determined by β‐galactosidase staining of embryos carrying the Lmx1b3′ LacZ allele (Dunston et al., ). Whole embryos were stained overnight: (a) E9.5, (b) E10.5, (c) E11.5, (d) E12.5 and (e) E13.5. For (f) E14.5 and (g–i) E15.5, embryos were partially dissected to allow for more efficient staining. (g) E15.5 forelimb. (h) E15.5 trunk and hindlimbs. (i) E15.5 head. Transverse views of the rostral spinal cord of β‐galactosidase stained Lmx1b3′ LacZ embryos; (j) E10.5, (k and l) E11.5, (m) E12.5, (n) E13.5 and (o) E15.5 embryos. Expression was analysed by β‐galactosidase staining except for (l) which is in situ hybridisation of the Lmx1b mRNA at E11.5 to be compared to panel (k). Lmx1b expression in kidney and mammary gland; (p) Kidney expression at E14.5 visualised by β‐galactosidase staining shows expression in glomeruli, (q) HandE stained section at 20X magnification showing mammary gland expression in an E15.5 embryo. Lmx1b appears to be uniformly expressed throughout the mammary gland primordium. Arrowhead: isthmus and location of Lmx1b expression at the midbrain–hindbrain junction (a); Arrow: mammary gland expression (c)100. Floor plate, fp; Central canal, cc; dorsal, D and ventral, V. Dorsal is on top for sections j–o. Reproduced with permission from McIntosh et al..

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Further Reading

Dai JX, Johnson RL and Ding YQ (2009) Manifold functions of the nail–patella syndrome gene Lmx1b in vertebrate development. Development Growth Differentiation 51: 241–250.

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Lee B and Morello R (2004) LMX1B and the nail patella syndrome. In: Epstein CJ, Erickson RP and Wynshaw‐Boris A (eds) Inborn errors of development, pp. 615–624. New York: Oxford University Press.

Sweeney E, Hoover‐Fong JE and McIntosh I (2009) Nail–patella syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K and Adam MP (eds) GeneReviews™ [Internet], p. 1993. Seattle (WA): University of Washington, Seattle.

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McIntosh, Iain(Nov 2012) Molecular Genetics of Nail–Patella Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024340]